The compound 6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline (compound (I) herein) is disclosed in co-pending application PCT/US2006/048241 published as WO 2007/075567. Compound (I) is a protein tyrosine kinase modulator, particularly inhibitor of c-Met.
The hepatocyte growth factor (HGF) (also known as scatter factor) receptor, c-Met, is a receptor tyrosine kinase that regulates cell proliferation, morphogenesis, and motility. The c-Met gene is translated into a 170 kD protein that is processed into a cell surface receptor composed of a 140 kD β transmembrane subunit and 50 kD glycosylated extra cellular α subunit.
Mutations in c-Met, over-expression of c-Met and/or HGF/SF, expression of c-Met and HGF/SF by the same cell, and over-expression and/or aberrant c-Met signalling is present in a variety of human solid tumours and is believed to participate in angiogenesis, tumour development, invasion, and metastasis. Cell lines with uncontrolled c-Met activation, for example, are both highly invasive and metastatic. A notable difference between normal and transformed cells expressing c-Met receptor is that phosphorylation of the tyrosine kinase domain in tumour cells is often independent of the presence of ligand.
C-Met mutations/alterations have been identified in a number of human diseases, including tumours and cancers—for instance, hereditary and sporadic human papillary renal carcinomas, breast cancer, colorectal cancer optionally with liver metastases, gastric carcinoma, glioma, ovarian cancer, hepatocellular carcinoma, head and neck squamous cell carcinomas, testicular carcinoma, basal cell carcinoma, liver carcinoma, sarcoma, malignant pleural mesothelioma, melanoma, multiple myeloma, osteosarcoma, pancreatic cancer, prostate cancer, synovial sarcoma, thyroid carcinoma, non-small cell lung cancer (NSCLC) and small cell lung cancer, transitional cell carcinoma of urinary bladder, testicular carcinoma, basal cell carcinoma, liver carcinoma—and leukemias, lymphomas, and myelomas—for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), multiple myeloma, (MM), myeloid sarcoma, non-Hodgkin's lymphoma and Hodgkin's disease (also called Hodgkin's lymphoma).
Over-expression of c-Met is also believed to be a potentially useful predictor for the prognosis of certain diseases, such as, for example, breast cancer, non-small cell lung carcinoma, pancreatic endocrine neoplasms, prostate cancer, oesophageal adenocarcinoma, colorectal cancer, salivary gland carcinoma, diffuse large B-cell lymphoma and endometrial carcinoma.
Because of the role of aberrant HGF/SF-Met signalling in the pathogenesis of various human cancers, inhibitors of c-Met receptor tyrosine kinase, including compound (I), have broad applications in the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype, including those in which c-Met is not over-expressed or otherwise altered. Inhibitors of c-Met also inhibit angiogenesis and therefore are believed to have utility in the treatment of diseases associated with the formation of new vasculature, such as rheumatoid arthritis and retinopathy (Michieli et al. P. 2004. Cancer Cell 6(1): 61-73).
PCT/US2006/048241 (WO 2007/075567) disclosed a method for preparing compound (I), wherein in the last step 2,2-difluoro-2-quinolin-6-ylacetohydrazide and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine were refluxed in 1-butanol for extended periods of time to afford compound (I) (Albright, J. D., et al. 1981. J. Med. Chem. 24: 592-600) However, these relatively harsh reaction conditions could lead to formation of side products, in particular butyl difluoro(quinolin-6-yl)acetate and 3-butoxy-6-(1-methyl-1H-pyrazol-4-yl)pyridazine. Hence, subsequent to the reaction, compound (I) needed to be purified by repeated chromatography, which could reduce the yield and hamper the upscalability of the above preparation method.
Accordingly, there exists a need to provide improved methods for preparing compound (I), in particular methods which may allow for improved yield, higher purity, less manipulation and/or better upscalability of the production process.
Crystalline polymorphs and hydrates represent different solid state molecular forms of the same compound. Different crystalline polymorphs and hydrates display different crystal structures due to different packing of the molecules in the lattice. This results in different crystal symmetry and/or unit cell parameters, which directly influence the physical properties.
Crystalline polymorphic forms and hydrates are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form or hydrate is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form or hydrate in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms or hydrates may exhibit enhanced thermodynamic stability, enhanced chemical stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs or hydrates may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, enhanced rates of dissolution due to different lattice energies, and improved (oral) bioavailability, etc.
Accordingly, there exists a need to obtain discrete and characterised polymorphic forms and hydrates of compound (I), especially wherein such forms may entail improved properties.
Salts also represent different molecular forms of a compound. Certain salt forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain salts may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, enhanced rates of dissolution due to different lattice energies, and improved (oral) bioavailability, etc.
Hence, there exists a need to obtain further salt forms of compound (I), especially wherein such forms may entail improved properties.